Up- and down-modulation of liver cytochrome P450 activities and associated events in two murine malaria models

De-Oliveira Ana, Carvalho, Paixão, Tavares, Gueiros, Siqueira, Paumgartten

Description

The mechanisms by which malaria up and down-regulates CYP activities are not understood yet. It is also unclear whether CYP activities are modulated during non-lethal malaria infections. This study was undertaken to evaluate the time course of CYP alterations in lethal ( Plasmodium berghei ANKA) and non-lethal ( Plasmodium chabaudi chabaudi ) murine malaria. Additionally, hypotheses on the association of CYP depression with enhanced nitric oxide (NO) production, and of CYP2a5 induction with endoplasmic reticulum dysfunction, enhanced haem metabolism and oxidative stress were examined as well. Methods Female DBA-2 and C57BL/6 mice were infected with P.berghei ANKA or P . chabaudi and killed at different post-infection days. Infection was monitored by parasitaemia rates and clinical signs. NO levels were measured in the serum. Activities of CYP1a (ethoxyresorufin- O -deethylase), 2b (benzyloxyresorufin- O -debenzylase), 2a5 (coumarin-7-hydroxylase) and uridine-diphosphoglucuronyl-transferase (UGT) were determined in liver microsomes. Glutathione-S-transferase (GST) activity and concentrations of gluthatione (GSH) and thiobarbituric acid-reactive substances (TBARS) were determined in the liver. Levels of glucose-regulated protein 78 (GRP78) were evaluated by immunoblotting, while mRNAs of haemoxygenase-1 (HO-1) and inducible nitric oxide synthase (iNOS) were determined by quantitative RT-PCR. Results Plasmodium berghei depressed CYP1a and 2b and induced 2a5 in DBA-2 mice. In P.berghei -infected C57BL/6 mice CYP activities remained unaltered. In both strains, GST and UGT were not affected by P.berghei . Plasmodium c . chabaudi depressed CYP1a and 2b and induced 2a5 activities on the day of peak parasitaemia or near this day. CYP2a5 induction was associated with over-expression of HO-1 and enhanced oxidative stress, but it was not associated with GRP78 induction, a marker of endoplasmic reticulum stress. Plasmodium chabaudi increased serum NO on days near the parasitaemia peak in both strains. Although not elevating serum NO, P.berghei enhanced iNOS mRNA expression in the liver. Conclusion Down-regulation of CYP1a and 2b and induction of 2a5 occurred in lethal and non-lethal infections when parasitaemia rates were high. A contribution of NO for depression of CYP2b cannot be ruled out. Results were consistent with the view that CYP2a5 and HO-1 are concurrently up-regulated and suggested that CYP2a5 induction may occur in the absence of enhanced endoplasmic reticulum stress.

Informations

• Publié par: biomed
• Publié le: 01 janvier 2010
• Nombre de lectures: 6
• Langue: English
• Poids de l'ouvrage: 1 Mo

Extrait

DeOliveiraet al.Malaria Journal2010,9:81 http://www.malariajournal.com/content/9/1/81

R E S E A R C HOpen Access Up and downmodulation of liver cytochrome P450 activities and associated events in two murine malaria models * Ana Cecilia AX DeOliveira , Renato S Carvalho, Flavio HM Paixão, Hellen S Tavares, Luciana S Gueiros, Carolina M Siqueira, Francisco JR Paumgartten

Abstract Background:The mechanisms by which malaria up and downregulates CYP activities are not understood yet. It is also unclear whether CYP activities are modulated during nonlethal malaria infections. This study was undertaken to evaluate the time course of CYP alterations in lethal (Plasmodium bergheiANKA) and nonlethal (Plasmodium chabaudi chabaudi) murine malaria. Additionally, hypotheses on the association of CYP depression with enhanced nitric oxide (NO) production, and of CYP2a5 induction with endoplasmic reticulum dysfunction, enhanced haem metabolism and oxidative stress were examined as well. Methods:Female DBA2 and C57BL/6 mice were infected withP.bergheiANKA orP.chabaudiand killed at different postinfection days. Infection was monitored by parasitaemia rates and clinical signs. NO levels were measured in the serum. Activities of CYP1a (ethoxyresorufinOdeethylase), 2b (benzyloxyresorufinOdebenzylase), 2a5 (coumarin7hydroxylase) and uridinediphosphoglucuronyltransferase (UGT) were determined in liver microsomes. GlutathioneStransferase (GST) activity and concentrations of gluthatione (GSH) and thiobarbituric acidreactive substances (TBARS) were determined in the liver. Levels of glucoseregulated protein 78 (GRP78) were evaluated by immunoblotting, while mRNAs of haemoxygenase1 (HO1) and inducible nitric oxide synthase (iNOS) were determined by quantitative RTPCR. Results:Plasmodium bergheidepressed CYP1a and 2b and induced 2a5 in DBA2 mice. InP.bergheiinfected C57BL/ 6 mice CYP activities remained unaltered. In both strains, GST and UGT were not affected byP.berghei.Plasmodium c.chabaudidepressed CYP1a and 2b and induced 2a5 activities on the day of peak parasitaemia or near this day. CYP2a5 induction was associated with overexpression of HO1 and enhanced oxidative stress, but it was not associated with GRP78 induction, a marker of endoplasmic reticulum stress.Plasmodium chabaudiincreased serum NO on days near the parasitaemia peak in both strains. Although not elevating serum NO,P.bergheienhanced iNOS mRNA expression in the liver. Conclusion:Downregulation of CYP1a and 2b and induction of 2a5 occurred in lethal and nonlethal infections when parasitaemia rates were high. A contribution of NO for depression of CYP2b cannot be ruled out. Results were consistent with the view that CYP2a5 and HO1 are concurrently upregulated and suggested that CYP2a5 induction may occur in the absence of enhanced endoplasmic reticulum stress.

* Correspondence: [e-mail] Laboratory of Environmental Toxicology, Department of Biological Sciences, National School of Public Health, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil

© 2010 DeOliveira et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.